第2章：药物开发的连续性：从临床前到市场准入
同写意20岁庆！第五届全球生物医药前沿技术大会报名开启！“意”同创新，穿越周期。7月中旬，苏州金鸡湖畔，让我们与“新药写意人”一起为中国医药创新“同写意”！医药产品的开发过程，从（先导化合物）筛选到临床研究，再到最终上市，都遵循特定的步骤。这些步骤通常被称为产品开发连续体或新产品开发。本章将明确新（新型）药和生物制品（new(novel)pharmaceuticals and biopharmaceuticals）开发连续体的各个步骤。五步流程所有使用新药物质（新分子实体）（new drug substance (new molecular entity，NME)）生产的医药产品都要经过医药产品开发连续体的五个步骤（five steps of the medicinal product development continuum）：发现和开发（discovery and development）、临床前研究（preclinical research）、临床研究（clinical research）、机构审查（agency review）和市场准入（market access），包括上市后安全监测和报告（postmarketing safety monitoring and reporting）。新药（New drug substances）和新医药产品（new medicinal products）是在专利保护下开发的。在专利有效期内，专利申请持有人拥有产品的独家销售权（market exclusivity，市场独占权）。开发连续体的五个步骤如图Figure 2-1所示。下面描述的步骤可以按顺序进行，有些步骤会重叠。通常情况下，一个步骤的结果会被用来决定是否进入下一个步骤、返回上一个步骤一般是为了获取更多信息，或停止医药产品的开发。化学、制造和控制（CMC）过程是医药产品开发过程中不可或缺的一部分。这一过程确保药品的质量、一致性和安全性将在人体中进行评估，并最终批准销售和使用。CMC开发也被称为药物（生物制药）开发。其任务包括制剂开发（formulation development）、生产开发（manufacturing development）、确定产品特性（identifying product characteristics）、定义关键质量属性（defining critical quality attributes）、制剂检测（product testing）以及符合所有全球质量和监管要求的规范（specifications that meet all global quality and regulatory requirements），例如现行药品生产质量管理规范（current good manufacturing practices，cGMP）和人用药品国际注册技术要求协调会（ICH）指南。CMC 开发有其自身的连续性、其时间表、资源和成本，必须与开发连续性活动（development continuum）并行。CMC开发始于步骤1，即化合物（药物或生物候选药物（drug or biologic candidate））确定后的发现和开发。由于CMC活动贯穿于开发（development）、商业投放（commercial launch）和授权后（post-authorization）的每个阶段，因此CMC连续体（CMC continuum）与阶段相适应，并在产品开发连续体（product development continuum）中变得更加复杂和昂贵。必须确定CMC任务，并将其纳入医药产品开发连续体的规划中，否则它们可能会对计划时间表或授权造成风险。CMC连续体中的任务也可能按顺序进行，并经常重叠。关键是CMC与产品开发的连续性并行不悖，以确保每个开发阶段都能获得按照适当质量标准生产的、其特性充分被研究的产品。在新药通过药物开发连续体并向监管机构提交上市许可申请（MAA）并获得批准后，专注于传统药物发现和开发的不同方法的公司就有机会了，即仿制药、生物类似药和再利用/重新定位。除生物类似药外，这些方法都是利用美国的505(b)(2)监管途径和欧盟的2001/83/EC指令4第10条，开发相同的活性成分（same active ingredient）或先前批准的活性成分（previously approved active ingredient），以寻找加快药物开发的机会。仿制药（Generic medicines）和治疗性蛋白质生物类似药（therapeutic protein biosimilars）是不遵循传统产品开发连续性的产品开发方法的例子。当创新药（innovator’s patent(s)）的专利或其他独占期到期时，仿制药和生物类似药生产商可向各自的监管机构提交美国505(b)(2)新药申请 (new drug application，NDA) 和仿制药药申请（abbreviated new drug application，ANDA）、加拿大简略新药申请（abbreviated new drug submission，ANDS）、欧盟MAA或美国 351(k)，以寻求仿制药或生物类似药的授权。一个仿制药/药品在剂型、安全性、规格、给药途径、药品质量、性能特征和预期用途方面（dosage form, safety, strength, route of administration, quality, performance characteristics, and intended use）与原研药（brand name drug）相同或生物等效。例如，Iressa（吉非替尼）片最初于2015年7月13日在美国获准用于非小细胞肺癌（NSCLC）；它在美国被批准为仿制药吉非替尼片，在欧盟被批准为Gefitinib Mylan片。在欧盟，治疗用生物类似药不是仿制药。它被定义为在结构（structure）、生物活性（biological activity）和疗效（efficacy）、安全性（safety）和免疫原性方面（immunogenicity profile）与参照药品（reference product）（一种已获批准的生物药品）高度相似的生物制品。在美国，生物类似药也被定义为与FDA批准的现有参照产品高度相似且无临床意义差异的生物制品。生物类似药（biosimilar product）与参比产品（reference product）在临床非活性成分上（clinically inactive components）的细微差别是可以接受的，但必须证明在安全性（safety）、纯度（purity）和效力（potency）（安全性和有效性）方面与参比产品没有临床意义上的差异。欧洲在生物类似药授权方面处于领先地位。2006年4月，Sandoz GmbH公司的Omnitrope（促生长素）获得了欧盟委员会（EC）的市场授权，成为世界上第一个生物类似药，它是辉瑞公司的Genotropin（促生长素）的生物类似药。随后，日本和加拿大也于2009年获得授权。2015年3月6日，Sandoz获得美国首个生物类似药Zarxio（filgrastim-sndz）的授权，这是安进公司Neupogen（filgrastim）的生物类似药。上述方法充分利用了先前提交的药理学、制剂、安全性（毒理学）和先前的人用历时经验（previous human experience）信息，从而减少了开发时间、成本和资源，降低了产品在临床开发中失败的风险。这两种方法都不要求公司重复非临床研究（步骤2）。就通用方法（generic approach）而言，对于已经获得安全性和有效性认证的非活性成分或制剂（ inactive ingredients or formulations already authorized for safety and effectiveness），无需重复临床研究（步骤3）。仿制药（generic medicine）必须与创新原研药产品具有生物等效性。对于生物类似药（biosimilar），需要进行新的试验以证明与参比药品的相似性，从而确定人体药代动力学（暴露）（human pharmacokinetic (exposure)）和药效学（反应）（pharmacodynamic(response)），以及临床免疫原性（clinical immunogenicity）。此外，监管机构可能会要求对生物类似药进行新的安全性和有效性简短临床试验（a new abbreviated clinical trial for safety and effectiveness），以便获得生物类似药的授权（biosimilar to be authorized）。药物再利用（drug repurposing，DR）是传统药物（traditional drug）开发的另一种有效替代方法。药物再利用为现有药物确定新用途，并为新药物找到除最初用于治疗的疾病之外的新的治疗用途（therapeutic uses）。药物再利用也被称为重新定位（repositioning）、回收利用（recycling）、抢救（rescuing）和重新定位（reprofiling）。两个著名的DR成功案例是西地那非（以万艾可的名义上市）和沙利度胺。万艾可是无意或意外的再利用。在一项治疗心绞痛的潜在新药的临床试验中，辉瑞公司发现许多男性参与者报告了不寻常的副作用--勃起。在万艾可于1998年获得批准之前，还没有治疗勃起功能障碍的口服药物。西地那非最初是作为抗高血压药物开发的，现已被重新用于治疗勃起功能障碍和肺动脉高压。沙利度胺是20世纪50年代和60年代在欧洲广泛使用的一种治疗孕妇恶心的药物，因与严重的出生（胎儿肢体）缺陷有关而于1961年撤市。最近，研究表明，它是一种有效的治疗麻风病和多发性骨髓瘤。最近一个药物再利用（更具体地说是重新定位）的例子是Keytruda（pembrolizumab），这是一种抗PD-1抗体PD-1抗体，最初于2014年获批用于治疗晚期或不可切除的黑色素瘤。Keytruda随后被批准用于更多适应症，与已批准的疗法/治疗方法联合使用，以及用于不同的治疗环境。截至本文撰写之时，Keytruda已被用于治疗19种不同的癌症。全新开发流程（de novo development）有五个步骤，而DR流程有四个步骤：化合物选择和验证、临床开发、监管机构审查和授权、市场准入，包括上市后安全监测和报告。仿制药和生物类似药一样，药物再利用是利用已有的药理学、毒理学以及临床和安全性数据来确定潜在的药物再利用机会，从而减少开发时间、成本和产品在临床开发中的失败率。将新药开发计划与药物再利用计划相比，研发时间大大缩短。据估计，采用全新方法开发一种新药需要10-17年时间，而采用DR方法只需3-12年即可获得FDA或EMA的授权。成本也大不相同，药物再利用和全新开发的成本分别约为16亿美元和120亿美元。下图Figure 2-2比较了从头开始开发流程和再利用流程，分别说明了5个和4个步骤。无论采用哪种方法开发医药产品，开发过程中的各个步骤都是一个连续的过程。根据不同的靶点、适应症、药物新颖性等，开发过程可能处于靶点发现的第1步、临床前研究的第2步或临床研究的第3步。一旦超过第2步，药物开发的成功率通常取决于临床开发和第1阶段的进展情况。根据一项分析，一个医药产品从1期成功进入监管授权阶段平均需要10.5年。这期间包括2.3年的1期、3.6年的2期、3.3年的3期以及1.3年的监管审查和授权阶段。当然，阶段持续时间会因疾病领域和适应症、临床试验设计最佳实践以及患者资格和可用性等众多因素而有很大不同。图2-3显示了14个主要疾病领域从1期到授权的阶段转换持续时间。根据疾病领域的不同，各个阶段的持续时间也有显著差异。例如，肿瘤学和泌尿学的1期过渡期最长，均为2.7年。肿瘤学是唯一一个平均监管审查时间少于1年的治疗领域；0.8年的审查时间几乎是所有非肿瘤学适应症累计审查时间（1.4年）的一半。泌尿科候选药物的2期审查时间最长（5.0年）。除泌尿科外，其余治疗领域的平均持续时间接近3.6年。眼科是开展2期研究最快的疾病领域（2.9年）。在3期研究时间方面，心血管领域的3期研究时间最长，为4.2年。心血管试验的患者人数众多，对心血管结果的评估需要长期进行，这使得试验时间比其他流行病领域（如精神病学（2.8年））更长，后者通常使用评分量表问卷评估短期症状改善情况。医药产品开发是一个漫长而昂贵的过程，无法保证一定成功。然而，了解这些步骤并制定明确的产品开发计划（包括CMC）将有助于最大限度地减少延误和风险，并提高成功的概率。为此，下文提供了开发药品连续体中每个步骤的精简摘要，本书稍后将提供每个步骤的更多具体细节。1研发（Discovery)研发是开发连续体的第一步。从历史上看，发现包括从传统药物中或偶然发现活性成分。亚历山大-弗莱明于1928年发现青霉素就是一个例子。弗莱明当时正在研究葡萄球菌，一粒灰尘污染了他的一个培养皿。在这块霉菌周围，形成了一个透明的无菌区，弗莱明后来发现其中含有改变世界的抗生素青霉素。后来，人们针对已确定的药物靶点筛选了大量的小分子或草药产品，以确定具有高亲和力、表明具有潜在治疗效果的靶点。随着人类基因组测序的完成，反向药理学（reverse pharmacology）已成为鉴定新化合物的首选方法。第一步是提出一个假设，即调节人体内特定靶点的活性具有改变疾病的作用（disease-modifying effect）。然后，根据这一假设，对选定的目标进行深入表征，并在实验室中合成适合靶点的化合物。最后，筛选过程对大量化合物库进行测试，以确定其亲和性（affinity）、潜在功效（potential efficacy）和安全性（safety）。传统上，发现（候选化合物）包括以下五个部分：1、靶点识别和验证（Target Identification and Validation）发现阶段（discovery phase）的第一步是确定在疾病过程中起重要作用的治疗靶点。一个好的靶点涉及一个关键的生物途径（crucial biological pathway），有别于任何以前已知的靶点，具有广泛的功能（extensive functional）和结构特征（structural characterization）以及可药用性（druggability）。可药用性的特点是具有易于接近的结合位点（well-accessible binding site），并能与标准治疗分子（如小分子、生物制品）结合。治疗药物靶点可通过公开可用的文库（如Sanger全基因组CRISPR文库或HEAL靶点和化合物文库）确定。大多数已知的药物靶点都是蛋白质；不过，许多其他生物大分子也已被确认为靶点。例如，核糖核酸（RNA）就是反义寡核苷酸的一个关键靶点。然后进一步验证治疗靶点。靶点验证包括在靶点和疾病之间建立明确的联系，从而确认所选靶点在疾病表型中的功能作用，并确认对其进行修饰具有治疗效果。人类表皮生长因子受体2（HER2）就是已确定的疾病靶点的一个例子，它是一种表皮酪氨酸激酶，在某些类型的乳腺癌、卵巢癌和胃癌的病因中起着关键作用。市场上销售的多种单克隆抗体和小分子药物（如赫赛汀Herceptin、泰立沙Tykerb）都以这种受体为靶点。通过与HER2受体相互作用，这些化合物可阻止信号通路的激活，从而进一步促进恶性肿瘤的增殖。验证靶点的一种典型技术是通过阐明其功能，例如使用mRNA调节来抑制所选靶点的基因表达。药物申请人可通过观察表达的靶点减少所产生的表型效应，确认该靶点是否值得进一步开发。2、实验开发和筛选（Assay Development and Screening）靶点验证后，将开发化合物筛选实验。这些筛选试验可评估候选新药在细胞、分子和生化水平上的作用。其中一个例子是酶联免疫吸附试验（ELISA），其最简单的形式是将匹配的抗体与目标抗原结合。抗体与酶相连，然后在接下来的步骤中加入酶的底物。如果抗体与抗原的亲和力很高并发生结合，随后的反应就会产生可检测的信号（通常是颜色变化），这也可以进行定量评估。实验开发可能是一个漫长而耗时的过程--从几周到六个月不等--因为标准实验通常需要适应高通量筛选（HTS）中使用的较小体积，而高通量筛选是在高密度微孔板中进行的。3、高通量筛选（High Throughput Screening）高通量筛选利用机器人技术、数据处理/控制软件和先进的检测机制，快速进行成千上万次药理学、化学和基因测试，如ELISA、流式细胞术、荧光偏振和基于聚类规则间隔回文重复序列（CRISPR）的基因疗法测试。高通量筛选评估大型化合物库与所选靶点的亲和力。然后对高通量筛选数据进行分析，进一步确定和完善结构-活性（structure-activity）关系。此外，这些筛选还能提供初步信息，说明哪些化合物具有非选择性、细胞毒性和潜在的基因毒性，应从进一步筛选中剔除。4、中靶到先导（ Hit to Lead）在"中靶到先导"过程中，对中靶（即发现对研究靶点具有高亲和力）的化合物进行评估，并在结构上预先优化为先导化合物。5、先导化合物优化(Lead Optimization)在先导化合物优化过程中，对在"从中靶到先导"过程中发现的先导化合物进行再合成和进一步修饰，以提高亲和力和减少副作用。在先导优化过程中，药效（强度）、功效、选择性或生物利用度等潜在特性都会得到改善。此外，先导化合物优化还包括使用动物药效模型和计算机工具进行实验测试，以预测先导化合物的吸收、分布、代谢、排泄和毒性（ADMET），最终确定候选药物。在研发过程中，需要建立基本水平的质量控制，以确保所选先导候选药物具有充分的结构特征和可重复性。不过，不需要正式的质量体系（no formal quality system）；所有候选药物都是在非良好操作规范（non-good practice(GxP)）条件下生产和测试的。这一阶段的制剂开发活动很少，主要集中在制备一种制剂，使化合物能够在不干扰选定的测定法的情况下进行筛选。不过，在这一早期阶段可能会进行额外的制剂和生产可行性研究，以衡量入围候选药物的可开发性。如果不能以商业上可行的方式配制或制造有效的候选化合物，那么它可能毫无价值。因此，制剂可行性可作为选择可行候选药物的额外工具。在这一阶段使用的分析检测方法不需要经过全面验证（fully validated）。但仍应证明其适用性（fit for purpose），即应进行基本的鉴定，以证明测量结果具有高度的特异性、精确性和准确性。一旦一种化合物被确定为主要候选化合物（通常还有第二种化合物作为备用候选化合物），就会进入第二步，即临床前研究。2临床前研究（Preclinical Research）在启动人体1期临床试验之前，选定的先导候选药物要在相关动物（如啮齿动物、狗和灵长类动物）和体外模型（如使用患者组织的细胞培养物或测试抑制人ether-à-go-go相关基因（hERG）心脏钾通道的安全性药理学筛选）中进行广泛的特征描述，后者可预测潜在的心血管脱靶效应。动物和体外模型研究通常被称为非临床研究。临床前研究阶段的主要目标是确定首次人体试验（FIH）的安全起始剂量。首先，对所选候选先导药物的药理特性进行进一步研究。这些测试可再次确认其作用模式，并详细了解该分子如何与人体相互作用，产生预期和非预期的在靶（on-target）和脱靶效应（off-target effect）。药理学评估研究所选候选先导药物的药效学（PD）和药代动力学（PK）。一般来说，药效学研究药物对生物系统的影响（the effects of a drug on biological systems），药代动力学研究生物系统对药物的影响（the effects of biological systems on a drug），即药效学研究药物与生物受体的相互作用，药代动力学讨论药物在生物系统的吸收、分布、代谢和排泄（ADME）。药物PK决定了药物作用的起效时间、持续时间和强度，以及药物的代谢情况，对于开发有效的药物制剂至关重要（见Table 2-1）。本书第5章和第6章将详细讨论这些药理学研究。接下来，候选先导药物要进行广泛的毒理学特征研究，这有助于确定初步的安全性概况和人体安全起始剂量。一系列标准的毒理学和遗传毒性研究是启动临床试验的基础。这些研究必须在首次IND或临床试验申请（CTA）中提交，并构成监管机构授权进行FIH研究的基础。这些非临床研究有时被称为IND/CTA授权研究。上市申请（marketing authorization(MA)）需要致癌性和生殖发育毒性数据，通常与3期临床试验同时进行（见Table 2-2）。并非所有的治疗方式都需要上述所有的评估--尤其是生物制品，在这种情况下，简单的非临床研究可能就足够了。需要强调的是，用于1期临床前研究的product（test article）研究产品（试验品）必须能够代表用于1期临床试验的研究产品，以便为临床使用的产品提供药代动力学和毒代动力学特征。因此，虽然在临床前1期临床试验中不要求使用GMP质量的材料（GMP-quality material），但在研究用药的生产和测试中应建立基本的质量体系，以确保充分的可追溯性和记录。临床前研究中使用的研究产品通常称为非GMP材料(non-GMP material)或毒理批次（tox batches）。在此阶段使用的制剂应尽可能接近拟议的临床制剂，或至少显示出与拟议的临床GMP材料相当的暴露情况（即暴露水平和持续时间、给药途径）。此外，还必须对研究药物的关键特性进行分析鉴定。分析表征的范围取决于治疗方式，生物制品的分析表征通常比小分子药物要广泛得多。与发现(discovery)阶段一样，分析方法不需要完全验证，但确实需要适合目的或合格（如上所述）。在1期临床前研究中使用的任何生物分析方法都需要进行全面的分析验证（Any bioanalytical methods used in Phase 1-enabling preclinical studies require full analytical validatio）。一旦1期临床前研究完成，该项目即进入临床研究阶段。3临床研究（Clinical Research）市场上的每一种治疗方法都需要经过多年的研究，包括临床研究。最简单地说，临床研究就是对人类健康和疾病的研究。临床研究是医药产品开发过程中必不可少的一部分，也是时间最长、成本最高的一步。临床研究以某种方式涉及人类参与者，本质上是将临床前研究转化为帮助患者的方法--为合适的患者找到合适的药物、合适的剂量。以人类志愿者或参与者为对象进行的临床研究称为临床试验或临床研究。这些术语通常可以互换。美国国立卫生研究院（NIH）于2014年将临床试验的定义修订为 "一项研究，在这项研究中，一名或多名受试者被前瞻性地分配到一项或多项干预措施（可能包括安慰剂或其他对照）中，以评估这些干预措施对健康相关的生物医学或行为结果的影响”。临床试验根据开发阶段的不同而有不同的目标；试验可调查拟议治疗方案的临床安全性和有效性，以及研究药物的药效学/药代动力学特征。临床试验最终会为全球监管机构的MA（上市许可）建立基本的安全性和有效性数据。研究新药的临床试验被称为介入性试验（interventional trials），因为其具有前瞻性，专门用于评估治疗或预防措施对疾病的直接影响。每种试验设计都有特定的结果测量指标。而观察性试验设计（Observational trial designs）通常是回顾性的，用于评估暴露-结果关系中的潜在因果关系。在极少数情况下，观察性研究可能有助于注册，因为其可以建立一个外部对照组，预测未接受治疗的患者群体的疾病进程，而不是让患者接触安慰剂。良好临床实践（GCP）是针对涉及人体的临床试验的设计、实施、执行、审计、记录、分析和报告的科学和道德质量标准。GCP确保临床试验的完整性以及受试者（参与者）的安全和福祉得到保护。2016年11月9日，ICH通过了《良好临床实践指南》E6（修订版2）；E6（修订版3）的修订工作正在进行中。此外，ICH 还发布了多份临床指南，涵盖特定患者人群和适应症试验以及生物统计评估等主题，以在全球范围内规范临床实践。除ICH指南外，各国机构还发布了许多其他指南和思考文件，规定了临床试验行为的最低质量标准和原则。（1）临床试验概述人体临床试验分阶段进行（见Figure 2-4）。每个阶段都旨在回答一个单独的研究问题，并收集有关新疗法的具体信息，如给药途径（如药片、溶液、注射剂）、给药方案和时间安排、安全性和疗效结果。第16章将深入介绍临床试验过程（笔者后续将陆续按次提供）。临床研究途径通常是线性进展，但有些临床项目可能包括一个以上的阶段，尤其是罕见病和重大未满足医疗需求的临床项目。每个阶段的信息都用于为下一阶段提供依据，并决定是否继续进行临床研究、返回前一阶段收集更多信息（如PK或生物利用度）或停止研究药物的开发。• 0期（Phase 0）0期试验（1期前研究或探索性研究）旨在通过在健康的人类志愿者身上获得初步数据，了解药物的性能是否符合临床前研究的预期，从而加快有潜力药物的开发。不需要/强制进行0期试验。0期试验不提供安全性或疗效数据，因为剂量太小，无法产生治疗效果（微剂量研究）。0期试验的规模非常小，参与者少于15人，给药时间很短。进行这些试验的目的通常是对候选药物进行排序，以确定哪种候选药物的PK参数最佳，从而进入进一步的开发阶段。如果医药产品的作用与预期不同，可能会进行更多的临床前研究。• 1期临床（Phase 1）通常情况下，1期或FIH试验是人类首次接触研究药物的阶段。新疗法的FIH试验已确定在动物身上使用是安全（无毒）的，通常在一小批健康的人类志愿者（即 20-100名受试者）中进行。在某些情况下，例如对于罕见疾病、肿瘤产品或针对致命的、未满足的医疗需求的高毒性治疗方法，也可能在疾病患者中进行1期试验。1期试验的主要目的是初步确定试验用医药产品的安全性，确定不造成伤害的最高给药剂量，即人体最大耐受剂量（MTD），并证明受试者能够耐受试验用药。此外，1期试验通常评估研究药物的药效学（PD）或“药物对机体的作用”和药代动力学（PK）谱或“机体对药物的作用”，其中还可能包括专门的1期试验，例如用于确定药物代谢和其他PK参数的放射性标记研究、心血管安全性研究、肝肾功能损害研究以及药物相互作用研究。1期试验用于确定最合适的给药途径（如片剂、溶液、注射剂）、足够的剂量和给药时间。1期试验通常会观察到初步的疗效迹象，但不是主要终点。1期试验通常都存在。• 2期（Phase 2)在1期试验结果的基础上，2期试验拟议适应症疾病或病症的患者施用研究药物。2期试验通常在多个地点进行，有几百名参与者（100-300人）参与，旨在评估预后终点，确定初步的疗效证据，并确定适当的剂量和给药计划，以便在第3期进行评估和确认。2期试验通常持续约2年。2期试验通常被称为非关键性试验或先导性试验（non-pivotal or pilot trials）。有时，2期试验会分为2a期和2b期试验。2a期试验侧重于剂量要求（dosing requirements），而2b期试验则特别侧重于疗效，如治疗、预防或诊断疾病（efficacy, e.g., treating,preventing, ordiagnosing the disease.）。在2a期试验中，少数参与者在该剂量下的安全性得到确认后，会多次服用试验药物，以确定剂量-反应关系（dose-response relationship）。也就是说，药物反应的增加是否与剂量有关。此外，还要确定获得最佳反应的给药频率。这一步骤被称为概念验证（proof of concept，POC）或原理验证 (proof of principle，POP)，将1期与剂量测定研究联系起来。POC研究是一项重要的临床开发成功标准，因为它证明了与相关靶点有关的可测量生物效应（measurable biological effect related to the target of interest）。在后期临床试验中，这种效应可以合理地转化为有临床意义的效应。与2a期相比，2b期的参与人数更多，其主要目的是找到副作用最小的最佳剂量（剂量反应研究），同时保持治疗效果（疗效），这是药物开发连续过程中的关键一步，被称为确定剂量范围的试验。正确的剂量对药物的疗效至关重要。2b期临床试验以单剂量递增试验（SAD）和多剂量递增试验（MAD）的形式对剂量递增进行评估，以确定最佳剂量（optimal dosage）和给药方案（dosing schedule），供3期临床试验确认。• 3期（Phase 3)在3期试验中，将根据所研究的病症，让更多的受试者（300到3000人）服用研究药物，以确认其有效性、监测副作用、将其与现行护理标准进行比较，并收集信息，以便安全使用该产品。3期试验通常持续约1-4年。3期试验通常是随机、多中心试验，通常持续时间较长，有时甚至长达数年（1-4）。随机试验会随机分配受试者使用研究药物或已获批准的药物（通常是标准治疗药物），如果没有现行治疗方法，则分配受试者接受安慰剂。3期试验通常采用双盲法；受试者和研究人员都不知道分配的是哪种治疗方法。随机化有助于消除解释结果时的偏差。3期试验是支持商业上市许可和标签的关键性安全性和有效性试验，确定了上市剂量和实际使用条件。由于3期试验的范围更广、时间更长，因此试验结果更有可能发现长期或罕见的副作用。虽然3期试验通常被称为关键性或注册性试验，但第1-3期试验的所有数据都要提交监管部门审查。• 4期（Phase 4)获得授权后，通常会在上市后安全评估或监督的范围内进行上市授权后试验，或者作为授权条件的结果。4期临床试验也是为了收集更多有关药物预期非预期效果的信息，检查药物在现实生活中和更大用户群中的表现，确定长期的益处和风险，并确定任何罕见的副作用。试验可能涉及被一般排除在临床试验之外的特定或不同的患者人群（如孕妇或哺乳期妇女），或确认与获批患者人群长期使用药物有关的副作用。如果以前的临床试验在彻底评估可能影响药物性能的因素方面受到限制，那么4期试验可用于更彻底地评估这些因素。例如，临床试验参与者可能被要求严格遵守饮食和用药方案。相比之下，4期试验是在普通人群中进行的，受试者可能会服用各种食物和其他药物。4期试验也可用于为已批准的药物寻找新的适应症（再利用或再加工）。一旦确定了新的适应症，根据适应症和现有的支持性信息，支持已批准药物的临床试验将在2期或3期进入药物开发连续体（ enter the drug development continuum）。由于3期试验是在人群较少、控制良好的试验条件下进行的，因此在获得授权后的试验中可以看到以前未曾发现的有害影响。根据最初授权时和支持性3期试验中未报告的新安全数据，一些药品被撤出市场。例如，止痛药罗非昔布（Vioxx）在一项新适应症的3期试验中显示，在长期治疗（18个月）期间，发生严重心血管事件（包括心脏病发作和中风）的相对风险增加。默克公司随后宣布在全球范围内自愿从市场上撤下Vioxx。3期确证试验（confirmatory trials）的结果是进入第4步（机构审查和上市许可）的关键。临床研究和开发连续体的临床试验阶段，包括行为和目标，将在第4节中详细讨论。4机构审查和上市许可（Agency Review and Marketing Authorization）如果从（起始的）研发、临床前研究、临床研究和CMC开发中获得的所有数据和证据都证明药品对其预期用途是安全有效的，并且产品开发商已充分描述了药品的特性，包括质量、规格、纯度、效价和稳定性属性（ quality, strength, purity, potency, and stability attributes），并且药品可以重复生产、测试和供应，那么产品开发连续体将进入第4步，即机构审查和上市许可。在第4步中，申请人汇编所有相关信息，证明药品安全有效、质量适当，并向监管机构（如美国FDA、欧洲药品管理局（EMA）、巴西卫生监管局（ANVISA）等）提交上市许可申请（MAA，也称为监管档案），请求批准产品上市。MAA必须包括从临床前研究到3期确证临床试验的数据和报告，以及符合该地区法规的药品CMC信息。全球有150多个监管机构对各个地区的医疗保健产品进行监管。每个地区都有监管要求，医药产品必须符合这些要求才能获得授权。这意味着开发人员和申办方必须了解每个地区的要求，并制作多份文件提交给不同的监管机构，从而增加了产品开发的复杂性。由于认识到国际上现有技术要求的多样性，1990年，ICH将美国、欧盟和日本的监管机构以及制药行业代表召集在一起，讨论药品的科学和技术问题，目的是在这些地区制定统一的监管要求和指导方针。从那时起，ICH制定了许多关于安全、质量和疗效主题的指导方针。这些指南已被全球越来越多的监管机构采用。如今，ICH已进入第四个十年，ICH正努力将协调范围扩大到创始地区以外。2003年定稿的《通用技术文件》（CTD）在很大程度上统一了医药产品授权的技术要求。各方一致同意以通用格式组织所有安全性、有效性和质量信息，以生成结构合理的监管档案，从而无需对提交给不同监管机构的信息进行重新格式化。值得注意的是，CTD并不涉及提交给监管机构的信息内容。CTD从根本上改变了监管审查程序和实践。CTD是加拿大、日本、欧盟、美国和澳大利亚等主要市场上市许可申请（MAA）的强制提交格式。包括中东和北非（MENA）在内的其他地区正在实施CTD，包括成功实施电子CTD（eCTD）规范。例如，自2015年以来，沙特阿拉伯、约旦和卡塔尔已经实施了eCTD格。CTD分为五个模块（见Figure 2-5）。模块1针对特定地区，提供无法统一的信息。它包括行政信息，如申请表和说明书（包括处方信息和建议在该地区使用的说明书）。模块2-5旨在统一所有地区的信息，是CTD的主体。模块2包含CTD摘要，基本上是模块3-5的概述和摘要。模块3包含质量和CMC信息，介绍如何按照 GMP和质量法规开发、生产、控制和放行药品。模块4包含非临床信息（包括研究报告），模块5包含临床研究信息（包括研究报告和临床试验数据），以证明其对预期用途的安全性和有效性。ICH已为每个学科确定了准则，为每个类别分配了代码：Q（质量）、S（安全）和E（疗效）。同样在2003年，EMA开始接受eCTD，并于2010年成为集中程序申请（centralized procedure applications）的强制要求。2015年7月1日，EMA宣布不再接受申请集中程序的产品的纸质申请表。2017年，美国宣布所有新药申报都必须采用eCTD格式。在日本，药品和医疗器械管理局（PMDA）于2017年12月发布了eCTD植入指南。加拿大卫生部宣布，自2018年1月1日起，eCTD成为强制要求。在不同国家，eCTD正日益成为各种申报类型的强制要求。在按照某个国家特定要求撰写、格式化、汇编和发布上市许可申请（MAA）后，eCTD允许以电子方式向监管机构无缝自动提交CTD。eCTD为以电子方式执行 CTD提供了统一的技术解决方案。监管档案的提交是通过安全提供监管档案以供审查的"网关"方法进行的，例如欧盟电子提交网关（EU e Submissions Gateway）、美国电子提交网关 (US Electronic Submission Gateway ）(ECG)和加拿大卫生部的通用电子提交网关Health Canada’s Common Electronic Submission Gateway（CESG）。监管机构确认收到并确认监管档案材料齐全，可进行正式审查后，即接受档案材料，并开始进行全面、严格的审查。监管机构的审查小组可能包括科学家、化学家、生物学家、药理学家、毒理学家、统计学家和医生等专家（scientists, chemists,biologists, pharmacologists,toxicologists,statisticians,and physicians），他们开始审查申请人提供的证据，这些证据证明了药品的质量、安全性和预期用途的有效性，以及拟议的说明书。除了对药品按预期用途使用时的安全性和有效性做出关键决定外，还要对用于确保和保持产品质量的CMC进行评估，以证明这些流程足以在产品使用和到期期间保持其特性、纯度、规格、有效性和微生物控制。获得授权的关键还在于证明产品具有良好的效益-风险特征。对于新的分子实体（new molecular entities），在最终授权之前，监管机构可能会要求对生产设施进行检查，以核实质量信息，并确保设施符合cGMP，能够生产和供应安全的药品。尽管全球监管机构的目标相同--通过监管医药产品来保护公众健康，但审查MAA的流程和时限却各不相同。美国和欧盟拥有世界上最先进、最明确的监管体系。在美国，针对新分子实体的《处方药和用户收费法》（PDUFA）、针对生物类似药的《生物类似药用户收费修正案》（BSUFA）以及针对仿制药的《仿制药用户收费法》（GDUFDA）规定了审查费用和时间。行动日期可能是决定批准药物、不批准药物或在需要更多信息和足够审查时间时发出完整答复函。在欧盟，根据产品类型和目标国家的数量，分为集中审批流程（CP，Centralized Procedure）、分散审批流程（DCP，Decentralized Procedure）、互认流程 (MRP，Mutual Recognition Procedure)和国家流程（NP，National Procedure)。在欧盟（27个成员国）用于授权时，根据集中程序对MAA进行的评估通常长达210天，其中不包括要求申请人提供人用医药产品委员会（CHMP）补充信息时的审查周期暂停。CHMP是EMA负责人用药品的科学委员会，在对MAA 进行全面评估后，就药品是否可以获得授权提出科学意见。最终，CHMP发布的科学意见将送交EMA。EMA随后将意见送交欧盟委员会（EC），由欧盟委员会决定是否颁发MA（上市批准）。其他监管机构也在改进和加强其监管系统，协调进程仍在继续。监管机构认识到，患有严重或罕见疾病的患者可以比标准审查时间更快地获得潜在疗法，从而获得临床益处，这是对监管审查流程的一项重大改进。因此，全球各地的监管机构制定了加速开发（expedited development）和非标准审查与授权途径（non-standard review and authorization pathways），以促进治疗此类疾病的新药（如富替巴替尼、pembrolizumab）的开发。这些途径还鼓励医药产品开发商与监管机构之间尽早进行持续互动（encourage early and continued interactions between the medicinal product developer and the regulatory agencies）。FDA目前有4个加速计划项目:优先审查（priority review designation）、加速批准（accelerated authorization）、快速通道认定（fast track designation）和突破性疗法认定(breakthrough therapy designation，BTD)，旨在促进和加快新药的开发和审查，以满足在治疗严重或危及生命的疾病方面尚未得到满足的医疗需求。同样，欧洲药品管理局（EMA）也设立了PRIME（PRIority MEdicines），以支持针对未满足医疗需求的药品开发。通过PRIME，该机构向药品开发商提供早期和积极的支持，以优化生成有关药品益处和风险的可靠数据，并加快对药品申请的评估。日本药品管理局制定了“SAKIGAKE指定系统”，通过开展优先咨询、事先评估和优先审查以及“未批准药品快速授权计划"，促进日本的研发和早期临床研究/试验，旨在使具有显著预期疗效的创新医疗产品尽早得到实际应用。有关快速途径的更多详情，请参阅第23章（后续陆续提供）。获得任何全球监管机构的上市许可都是药品开发商产品开发过程中的一个重要里程碑，可以为全球患者提供治疗特定疾病的药物，并开发针对未满足医疗需求（unmet medical needs）（如罕见病）的创新药物。这一步通向产品开发连续体的第五步--市场准入，即在合适的时间以合适的价格向合适的患者提供医药产品。5市场准入（Market Access）医药产品开发的最终目标和重点是获得上市授权和商业化，使患者能够获得新的替代疗法或满足未满足的医疗需求。对于全球制药和生物技术公司来说，这就是市场准入（Market Access），通常被描述为以合适的价格在合适的时间向合适的患者提供合适的治疗。一旦药品获得批准并上市，处方医生和患者需要立即、持续地获得药品。通常情况下，市场准入和活动是在临近提交上市申请、获得授权和上市时规划的。然而，要取得成功，市场准入规划应该是从早期开发到上市后的整个过程的一部分，提供对目标产品概况和其他关键开发投入的投入，例如，患者偏好、生活质量指标、健康行为、症状和健康状况。（patient preferences, quality-of-life metrics, health behaviors, symptoms, and health status）。Figure 2-6说明了市场准入的重要作用。该简化模型显示了从监管授权到药品处方之间市场准入的主要考虑因素。虽然该模型显示的是药品获得批准后的市场准入顺序，但实际上，要想成功实施市场准入战略，需要更早地考虑这些因素。在患者获得药品之前，必须获得特定国家或国家卫生当局的监管授权。即使获得授权，患者也不一定能立即获得药品。在许多国家，首先需要确定国家定价和报销。例如，在欧盟国家，在获得上市许可后，通常会在国家层面进行卫生技术评估（health technology assessments, HTAs），用于指导定价和报销建议。报销并不总是有保障的。例如，2020年1月，英国国家健康与护理卓越研究所（NICE）建议不报销用于治疗难治性抑郁症的Spravato（艾司卡胺），原因是其临床成本和疗效存在不确定性。最近，2022年5月，加拿大药品和卫生技术局（CADTH）建议不报销Spinraza（nusinersen）治疗成人脊髓性肌萎缩症的费用，原因是缺乏针对18岁及以上SMA患者的临床试验。此外，地方、地区或医院层面的决策者可能多种多样。例如，一个国家可能有30种可报销的特许药物可用于治疗某种疾病。但是，如果当地的处方指南规定不能给病人开其中一种药，那么就不太可能给病人开这种药物。一旦这些关键要素到位，医生或其他处方人员就会发挥关键作用，根据临床指南、当地处方目录、先前患者对药物的反应、与治疗相关的症状（副作用）以及其他可用的治疗方法等因素，决定为患者开具哪种药物。这些因素还可能包括与健康相关的生活质量（quality of life ，QoL），它可以反映出患者对其身体、心理、社交和总体健康状况的看法。在意大利和西班牙，QoL数据在地区和地方层面非常重要，可用于纳入处方和指南。定价和报销与市场成功之间的关系如Figure 2-7所示。定价是药品的清单价格或全国价格，即支付给制造商的公布价格。价格可根据批发商的收费、谈判达成的折扣、奖励和其他协议进行调整。在美国，MAA持有者制定的价格不受监管。在许多其他国家，价格是根据其他国家的价格确定的。例如，法国、德国和英国的定价通常会被参考，并对其他国家的定价产生影响。在英国，通过国家医疗服务系统（NHS）报销药品受到NICE、苏格兰药品联合会（SMC）和全威尔士药品战略小组（AWMSG）的影响。在法国，卫生高级管理局（HAS）负责确定政府报销和患者支付的价格比例。在中国，目前没有报销制度。药品直接进入自由市场，由患者买单。报销也因国家而异。在许多欧洲国家，衡量新药与标准护理相比的相对有效性评估（REA）的HTA是报销的一项要求。与健康相关的QoL是公认的REA终点。然而，对于使用哪种QoL数据（如质量调整生命年或等值获得生命年）还缺乏共识。虽然以尽可能广泛的市场准入和最有利的定价为目标很重要，但确定药品对每个利益相关者的价值也很重要。医药产品开发公司目前正在将真实世界证据（RWE）工具纳入产品生命周期，以帮助实现成功上市和最佳市场准入，将合适的药物提供给合适的患者。最简单地说，真实世界证据就是利用分析方法为整个产品生命周期的决策提供信息和支持，这些分析方法提供了有关患者、不同临床表型和疾病负担的真实世界知识，而这在过去是不可能实现的。此外，真实世界证据还能促进比较有效性，帮助确定新产品的见解，并在广泛的结果（如用药依从性、患者满意度、资源利用率和相关成本）方面对产品进行区分，然后利用这些数据为目标产品简介提供信息，定义产品的特定属性，为临床试验设计（正确的疾病和患者人群）提供信息，并瞄准特定市场。临床医生和患者也在使用RWE来了解护理、效率和健康结果方面的进步。展望未来，RWE是一种在整个药物开发过程中越来越常用的工具，可最大限度地提高价值并增加市场成功的可能性。第31章“广告与促销”和第32章“市场准入”将更详细地讨论市场准入问题，包括定价与报销、广告及其他影响市场成功的因素：报销和定价。在市场准入的同时，MAA持有人还负责获批药品的上市后监管和生命周期管理。MAA持有人必须确保产品质量、安全性和有效性，并通过持续遵守cGMP法规和与质量体系相关的指南（包括产品投诉），减轻上市后对患者健康和安全的任何潜在影响。此外，MA持有者必须保持申请中有关标签、CMC更改（如生产或配方）和药物警戒（安全性）（包括不良事件报告）的最新信息。这些活动通常被归类为授权后活动，详见第6节：上市后授权（后续推文将提供）。— 结论 —医药产品开发是一个连续的过程，具有全球公认的特定步骤。这一过程漫长、复杂、成本高昂，并因不同国家的具体要求而更具挑战性。ICH继续致力于协调ICH创始地区以外的监管要求和指南，新兴市场正在采用和实施CTD和eCTD提交格式、ICH E8（R1）临床研究的一般考虑因素和ICH E6（R2）良好临床实践等标准。CMC开发是确保医药产品的质量、一致性、安全性和可用性的连续开发过程中不可或缺的一部分。上市授权是允许药品在授权地区销售的关键。然而，在许多国家，在开具处方和患者获得药品之前，需要确定并商定国家定价和报销。通常，这些决定也是在地方、区域或医院层面做出的。市场的成功需要考虑定价、报销和利益相关者（支付方、医生和患者）的需求。健康技术评估、与健康相关的生活质量指标和真实世界证据在产品开发过程中发挥着重要作用，并为临床试验设计、目标产品简介等提供意见，帮助确保以合适的价格为合适的患者开发出合适的药物。英文版原文（上下滑动查看更多）Chapter 2 The Drug Development Continuum, Preclinical to Market AccessThe medicinal product development process, from discovery through clinical investigation and ultimately to the market, follows specific steps. The collective steps often are referred to as the product development continuum or de novo product development. This chapter will identify the steps in the product development continuum of new (novel) pharmaceuticals and biopharmaceuticals.一、A Five-Step ProcessAll medicinal products manufactured with a new drug substance (new molecular entity) move through five steps of the medicinal product development continuum: discovery and development, preclinical research, clinical research, agency review, and market access, including postmarketing safety monitoring and reporting.New drug substances and new medicinal products are developed under patent protection. While the patent is in effect, the application holder retains exclusive rights to market the product (market exclusivity).The five steps in the development continuum are illustrated in Figure 2-1. The steps described below may proceed sequentially, and some steps will overlap. Often, the output of one step is used to make decisions to proceed to the next step, move back to the previous step to generate more information, or stop the development of the medicinal product.An integral part of the medicinal product development continuum is the chemistry, manufacturing, and controls (CMC) process. This process ensures that the quality, consistency, and safety of the medicinal product will be evaluated in humans and ultimately approved for distribution and use. CMC development is also referred to as Pharmaceutical (Biopharmaceutical) development. The tasks include formulation development, manufacturing development, identifying product characteristics, defining critical quality attributes, product testing, and specifications that meet all global quality and regulatory requirements, e.g., current good manufacturing practices (cGMPs) and International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. CMC development has its own continuum, timeline, resources, and cost that must parallel the activities in the development continuum. CMC development begins in Step 1, discovery and development after a compound (drug or biologic candidate) is identified. The CMC continuum is phase-appropriate and becomes more complex and costly through the product development continuum because CMC activities continue through every stage of development, commercial launch, and post-authorization. The CMC tasks must be identified and included in the planning of the medicinal product development continuum, or they may become a risk to the program timeline or authorization. The tasks in the CMC continuum also may occur sequentially and often overlap. The key is that CMC parallels the product development continuum to ensure the availability of an adequately characterized product manufactured according to appropriate quality standards for each stage of development.After a new medicinal product has gone through the drug development continuum and the marketing authorization application (MAA) has been submitted to and approved by a regulatory agency, an opportunity becomes available for companies focused on different approaches to traditional drug discovery and development, i.e., generic medicines, biosimilars, and repurposing/repositioning. Except for biosimilars, these approaches develop the same active ingredient or previously approved active ingredient to identify opportunities to expedite drug development using a 505 (b)(2) regulatory pathway3 in the US and Article 10 of Directive 2001/83/EC4 in the EU.Generic medicines and therapeutic protein biosimilars, areexamples of product development approaches that do not follow the traditional product development continuum. When the innovator’s patent(s) or other periods of exclusivity expire, generic medicines and biosimilar manufacturers can submit applications 505 (b)(2) new drug application (NDA) and abbreviated new drug application (ANDA) in the US, abbreviated new drug submission (ANDS) in Canada, MAA in the EU, or 351(k) in the US to the respective regulatory agency to seek authorization for their generic or biosimilar version. A generic drug/medicine is identica – or bioequivalent – to the brand name drug in dosage form, safety, strength, route of administration, quality, performance characteristics, and intended use.For example, Iressa (gefitinib) tablets was authorized originally for non-small cell lung cancer (NSCLC) in the US on 13 July 2015; it is approved as the generic medicine gefitinib tablets in the US, and Gefitinib Mylan tablets in the EU.In the EU, a therapeutic biosimilar is not a generic medicine. It is defined as a biological medicine highly similar to the reference product, an already approved biological medicine, in terms of structure, biological activity and efficacy, safety, and immunogenicity profile. In the US, a biosimilar is also defined as a biological product that is highly similar to and has no clinically meaningful differences from an existing Food and Drug Administration (FDA) approved reference product. Minor differences between the biosimilar product and the reference product in clinically inactive components are acceptable and must demonstrate no clinically meaningful differences from the reference product in terms of safety, purity, and potency (safety and effectiveness).8 Europe has led the way in biosimilar authorizations. In April 2006, Sandoz GmbH received marketing authorization (MA) for Omnitrope (somatropin)9, a biosimilar to Pfizer’s Genotropin (somatropin), from the European Commission (EC), becoming the world’s first biosimilar. Japan and Canada followed with authorizations in 2009. On 06 March 2015, Sandoz received authorization for the first US biosimilar, Zarxio (filgrastim-sndz), a biosimilar to Amgen’s Neupogen (filgrastim).These above approaches leverage the information previously submitted for pharmacology, formulation, safety (toxicology), and previous human experience, thereby reducing development time, cost, and resources and reducing the risk of product failures in clinical development. The two approaches do not require the company to repeat nonclinical (Step 2) research. For a generic approach, clinical research (Step 3) is not repeated on inactive ingredients or formulations already authorized for safety and effectiveness. The generic medicine must be bioequivalent to the innovator reference product. For a biosimilar approach, new trials to demonstrate similarity to the reference medicine are conducted to determine human pharmacokinetic (exposure) and pharmacodynamic (response), and clinical immunogenicity. In addition, a regulatory agency may require a new abbreviated clinical trial for safety and effectiveness for the biosimilar to be authorized.Another effective alternative approach to traditional drug development is drug repurposing (DR). DR identifies new uses for existing drugs and finds new therapeutic uses for new drugs other than the disease for which it was initially intended. DR is also known as repositioning, recycling, rescuing, and reprofiling. Two well-known success stories of DR are sildenafil, marketed as Viagra, and thalidomide. Viagra represents unintended or accidental repurposing. During a clinical trial for a potential new drug to treat angina, Pfizer observed that many male participants reported unusual side effects, erections. Before Viagra was approved in 1998, there was no oral treatment for erectile dysfunction. Before Viagra was approved in 1998, there was no oral treatment for erectile dysfunction. Originally developed as an anti-hypertensive, sildenafil has been repurposed to treat erectile dysfunction and pulmonary arterial hypertension. Thalidomide, a widely used drug in Europe in the 1950s and 1960s for the treatment of nausea in pregnant women, was connected to serious birth (fetal limb) defects and removed from the market in 1961.12 Recently, research has shown it to be an effective treatment for leprosy and multiple myeloma.A more recent example of DR, more specifically repositioning, is Keytruda (pembrolizumab), an anti-PD-1 antibody originally approved in 2014 to treat advanced or unresectable melanoma. Keytruda subsequently has been approved for additional indications, in combination with approved therapies/treatments, and for use in different treatment settings. As of this writing, Keytruda was indicated to treat 19 different cancers.While the de novo development process has five steps, the DR process has four steps: compound selection and validation, clinical development, regulatory authority review and authorization, and market access, including postmarketing safety monitoring and reporting.As with generic medicines and biosimilars, DR leverages previously generated pharmacology, toxicology, and clinical and safety data to identify potential DR opportunities, reducing development time, cost, and rate of product failures in clinical development. When comparing the de novo medicinal product development program against a DR program, there is a substantial reduction in research and development time. In the de novo approach, it is estimated that it can take 10-17 years to develop a new drug compared to 3-12 years for authorization from FDA or European Medicines Agency (EMA) using the DR approach. The costs are also significantly different, approximately $1.6 billion versus $12 billion for DR and de novo development, respectively.15 Figure 2-2 compares the de novo development process versus repurposing, illustrating the 5 and 4 steps, respectively.Regardless of which approach is taken to develop a medicinal product, the steps in the development process are a continuum. Depending on the target, indication, drug novelty, etc., the development process may be at Step 1 for target discovery, Step 2 preclinical research, or Step 3 clinical research. Once beyond Step 2, the drug development success rate often depends on clinical development and progression from Phase 1.According to one analysis, it takes an average of 10.5 years for a medicinal product to successfully progress from Phase 1 to regulatory authorization. That period includes 2.3 years at Phase 1, 3.6 years at Phase 2, 3.3 years at Phase 3, and 1.3 years at the regulatory review and authorization stage.16 Of course, phase duration can vary greatly depending on numerous factors, including disease area and indication, clinical trial design best practices, and patient eligibility and availability. 2-3 shows the phase transition duration from Phase 1 to authorization in 14 major disease areas. There are noteworthy differences in duration within individual phases based on disease area. For example, oncology and urology share the longest Phase 1 transition at 2.7 years. Oncology is the only therapeutic area with an average regulatory review of less than 1 year; the 0.8-year duration is almost half as short as the cumulative total for all non-oncology indications (1.4 years). Urology drug candidates see the longest Phase 2 duration (5.0 years). Excluding urology, the remaining therapeutic areas lie close to the average duration of 3.6 years. Ophthalmology is the fastest disease area for Phase 2 research (2.9 years). When looking at Phase 3 timelines, cardiovascular has the longest Phase 3 timelines at 4.2 years. The large patient populations in cardiovascular trials and the long-term evaluation of cardiovascular outcomes contribute to longer timelines than seen in other prevalent disease areas, such as psychiatry (2.8 years), which typically assesses short-term symptomatic improvement using rating-scale questionnaires.The medicinal product development continuum is a lengthy and costly proposition with no guarantee of success. However, understanding the steps and developing a clear product development plan, including CMC, will help to minimize delays and risks and increase the probability of success. To that end, a high-level summary of each step in the development continuum is provided below, with more specific details for each step provided later in this book.• Step 1: DiscoveryDiscovery research is the first step in the development continuum. Historically, discovery involved identifying active ingredients in traditional medicines or simply by chance. An example is the discovery of penicillin by Alexander Fleming in 1928. Fleming was investigating staphylococcus bacteria, and a speck of dust contaminated one of his Petri dishes. Around the resulting patch of mold, a clear, bacteria-free zone formed, which Fleming later identified as containing the world-changing antibiotic penicillin.Later, large libraries of small molecules or herbal products were screened against established drug targets to identify those binding with high affinity, indicating a potential therapeutic effect.With the completion of the sequencing of the human genome, reverse pharmacology has become the preferred way of identifying new compounds. Here, the first step is the development of a hypothesis that the modulation of the activity of a specific target in the human body has a disease-modifying effect.Then, based on this hypothesis, the selected target is characterized in-depth, and compounds are tailor-made in the lab to fit the target.Finally, screening processes test large libraries of compounds for their affinity, potential efficacy, and safety.Traditionally, the discovery has included the following five parts:1. Target Identification and ValidationThe first step in the discovery phase is identifying a therapeutic target that plays a significant role in the disease process. A good target involves a crucial biological pathway, distinct from any previously known target, extensive functional and structural characterization, and druggability. Druggability is characterized by having a well-accessible binding site and being capable of binding standard therapeutic molecules (e.g., small molecules, biologics). Therapeutic drug targets can be identified via publicly available libraries, such as the Sanger Whole Genome CRISPR library or the HEAL Target and Compound Library. Most known drug targets are proteins; however, many other biomolecules have been validated as targets. An example is ribonucleic acid (RNA), a key target for antisense oligonucleotides.The therapeutic target is then further validated. Target validation involves establishing a clear link between the target and the disease, which confirms the functional role of the chosen target in the disease phenotype and confirms that its modification has a therapeutic effect. An example of an established disease target is the Human Epidermal Growth Factor Receptor 2 (HER2), an epidermal tyrosine kinase that plays a pivotal role in the etiology of certain types of breast, ovarian, and gastric cancers. This receptor is targeted by a broad range of marketed monoclonal antibodies and small molecules (e.g., Herceptin, Tykerb). By interaction with the HER2 receptor, these compounds prevent the activation of signaling pathways that further enhance the proliferation of malignant growth.A typical technique to validate targets is by elucidation of their function by, e.g., using mRNA modulation to suppress gene expression of the chosen target. A drug sponsor can confirm whether the target merits further development by observing the phenotypic effect that results from a decrease in the expressed target.2. Assay Development and ScreeningFollowing target validation, compound screening assays are developed. These screening assays are tests that evaluate the effects of the new drug candidate at the cellular, molecular, and biochemical levels. One example is the enzyme-linked immunosorbent assay (ELISA), which in its simplest form applies a matching antibody to the targeted antigen so that it can bind to it. The antibody is linked to an enzyme, and in a following step, the enzyme’s substrate is added. If the antibody shows a high affinity to the antigen and binding occurs, a subsequent reaction produces a detectable signal (usually a color change), which can also be assessed quantitatively.Assay development can be a very long and time-consuming process – from several weeks to six months – because standard assays often need to be adapted to the smaller volumes used in high throughput screening (HTS), where processes are conducted in microtiter plates of high density.3. High Throughput ScreeningHTS uses robotics, data processing/control software, and sophisticated detection mechanisms to rapidly conduct thousands of pharmacological, chemical, and genetic tests, such as ELISA, flow cytometry, fluorescence polarization, and clustered regularly interspaced palindromic repeats (CRISPR)-based tests for gene-based therapies. HTS assesses large libraries of compounds for their affinity to the chosen target.HTS data are then analyzed to determine and refine further structure-activity relationships. In addition, these screens also provide preliminary information about which compounds are nonselective, cytotoxic, and potentially genotoxic and should be eliminated from further screening.4. Hit to LeadIn the hit to lead process, compounds that gave a hit, i.e., were found to have a high affinity against the investigated target, are evaluated and structurally pre-optimized into lead compounds.5. Lead OptimizationIn the lead optimization process, the lead compounds discovered in the hit to lead process are resynthesized and further modified to improve affinity and reduce side effects. Potential properties, such as potency (strength), efficacy, selectivity, or bioavailability, are improved during the lead optimization process. In addition, lead optimization includes experimental testing using animal efficacy models and in silico tools to predict the absorption, distribution, metabolism, excretion, and toxicity (ADMET) of the lead compound, leading to the ultimate drug candidate.During the discovery process, a basic level of quality control needs to be established to ensure adequate structural characterization and reproducibility of the chosen lead drug candidate. However, no formal quality system is required; all drug candidates are manufactured and tested under non-good practice (GxP) conditions. Formulation development activities at this stage are minimal and mainly are focused on preparing a formulation that allows the compound to be screened without interfering with the selected assays. However, additional formulation and manufacturing feasibility studies may have been undertaken at this early stage to gauge the developmentability of the short-listed candidates. An effective candidate may be worthless if it cannot be formulated or manufactured in a commercially viable manner. Thus, formulation feasibility may serve as an additional tool for choosing a viable candidate. Analytical assays used at this stage do not need to be fully validated. Still, it should be demonstrated that they are fit for purpose, i.e., they should undergo a basic qualification that demonstrates measurements will be specific, precise, and accurate with a high degree of certainty.Once a compound is identified as the lead candidate (often supported by a second compound as a backup candidate), it moves into Step 2, preclinical research.• Step 2: Preclinical ResearchBefore initiating Phase 1 clinical trials in human subjects, the chosen lead candidate undergoes extensive characterization in relevant animals, e.g., rodents, dogs, and primates, as well as in vitro models,such as cell cultures using patient-derived tissues or safety pharmacology screens testing inhibition of the human ether-à-go-go-related gene (hERG) cardiac potassium channel, which is predictive of potential cardiovascular off-target effects. Studies in animal and in vitro models are usually referred to as nonclinical studies.The main objective of the preclinical research phase is the determination of a safe starting dose for the first-in-human (FIH) study. First, the pharmacologic properties of the chosen lead candidate are further investigated. These tests reconfirm the mode of action and allow the development of a detailed understanding of how the molecule interacts with the body at the desired and non-desired on-target and off-target effect.The pharmacology evaluation investigates the pharmacodynamics (PD) and pharmacokinetics (PK) of the chosen lead candidate. Generally speaking, PD studies the effects of a drug on biological systems, and PK studies the effects of biological systems on a drug, i.e., pharmacodynamics investigates the interaction with biological receptors, and PK discusses the absorption, distribution, metabolism, and excretion (ADME) of the drug from the biological system. Drug PK determines the onset, duration, and intensity of a drug’s effect and its metabolic profile and is vital to developing an efficacious drug formulation (see Table 2-1). These pharmacology studies are discussed in more detail in Chapters 5 and 6 of this book.Next, the lead candidate undergoes an extensive toxicology characterization, which helps to establish a preliminary safety profile and a safe starting dose in humans. A standard battery of toxicology and genotoxicity studies form the basis for initiating clinical trials. These studies must be submitted in the original IND or clinical trial application (CTA) and form the basis of the regulatory agency authorization to proceed with the FIH study. These nonclinical studies sometimes are referred to as IND/CTA enabling studies. Data on carcinogenicity and reproductive developmental toxicity are needed for MA and are typically conducted in parallel with Phase 3 clinical trials (see Table 2-2). Not all of the evaluations described above are required for all therapeutic modalities – especially for biological products where an abbreviated nonclinical program may be adequate.It should be highlighted that the investigational product (test article) used in Phase 1-enabling preclinical studies needs to be representative of the investigational product used in Phase 1 clinical trials to provide a pharmacokinetic and toxicokinetic profile representative for the product to be used in the clinic. Thus, while the use of GMP-quality material is not required in the preclinical Phase 1-enabling trials, an essential quality system should be in place for the manufacture and testing of the investigational medicine to ensure adequate traceability and records. The investigational product used in the preclinical studies is typically referred to as non-GMP material or tox batches. The formulation used at this stage should be as close as possible to the proposed clinical formulation or at least demonstrate an exposure scenario (i.e., level and duration of exposure, route of administration) comparable to the proposed clinical GMP material.In addition, an analytical characterization capturing critical properties of the investigational medicine must be performed. The extent of the analytical characterization depends on the therapeutic modality and is usually far more extensive for biological products than small molecule drugs. Like at the discovery stage, analytical methods do not need to be fully validated but do need to be fit-for-purpose or qualified, as described above. Any bioanalytical methods used in Phase 1-enabling preclinical studies require full analytical validation. Once Phase 1-enabling preclinical studies are completed, the program moves into clinical research.• Step 3: Clinical ResearchEvery treatment on the market takes years of research, including clinical research. In its simplest terms, clinical research is the study of human health and disease. Clinical research is an essential part of the medicinal product development continuum and is the longest and most expensive step. Clinical research involves human participants in some way, essentially translating preclinical research into finding ways to help patients – finding the right drug, at the right dose, for the right patient.Clinical research conducted on human volunteers or participants is called a clinical trial or clinical study. These terms usually are interchangeable. The US National Institutes of Health (NIH) in 2014 revised the definition of a clinical trial to “a research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes.”19 Clinical trials in human subjects are conducted to investigate whether a new medicinal product is safe and effective to treat, prevent or diagnose a disease in a particular patient population. Clinical trials may have different objectives depending on the phase of development; trials may investigate the clinical safety and efficacy of a proposed treatment regimen and the pharmacodynamic/pharmacokinetic characteristics of an investigational medicine. Clinical trials ultimately establish the essential safety and efficacy data for MA by global regulatory agencies.Clinical trials investigating a new medicinal product are called interventional trials since they are prospective and specifically tailored to evaluate a direct impact of a treatment or preventive measure on disease. Each trial design has specific outcome measures. Observational trial designs, in contrast, are often retrospective and are used to assess potential causation in exposure-outcome relationships. In rare cases, observational studies may be registration-enabling as they may allow the building an external control group predicting the course of disease in a non-treated patient population in lieu of exposing patients to placebo.Good clinical practice (GCP) is a scientific and ethical quality standard for the design, conduct, performance, auditing, recordkeeping, analysis, and reporting of clinical trials involving human subjects. GCP ensures that the integrity of a clinical trial and the safety and well-being of trial subjects (participants) is protected. ICH adopted the Guideline for Good Clinical Practice E6 (Revision2), 9 November 2016; a revision to E6(R3) is in progress. In addition, ICH issued several clinical guidelines covering topics such as trials in specific patient populations and indications and biostatistical evaluation to standardize clinical practice globally.Apart from the ICH guidelines, national agencies have issued numerous other guidelines and reflection papers defining minimum quality standards and principles of clinical trial conduct.1.Clinical Trial OverviewClinical trials in human subjects are conducted in phases (see Figure 2-4). 22 Each phase is designed to answer a separate research question and to collect specific information about a new treatment, such as its delivery mechanism (e.g., pill, solution, injection), administration regimen and schedule, safety profile, and efficacy outcome(s). The clinical trial process is covered in depth in Chapter 16.The clinical research pathway is typically a linear progression, but some clinical programs may include more than one phase, especially for rare diseases and significant unmet medical needs.Information from each phase is used to inform the next phase and to decide whether to continue clinical research, to return to a previous phase to gather additional information, e.g., PK or bioavailability, or to stop development of the investigational medicine.（1）Phase 0A Phase 0 trial (Pre-Phase 1 or exploratory study) is designed to speed up the development of promising medicines by generating preliminary data in healthy human volunteers to see if the agent performs as expected based on the preclinical research. A Phase 0 trial is not required. The Phase 0 trial provides no safety or efficacy data because the dose is too low to produce a therapeutic effect (microdosing studies). Phase 0 trials are very small, with less than 15 participants, and the drug is administered for a short time.These trials are typically conducted to rank drug candidates to decide which candidate has the best PK parameters to move forward into further development. Additional preclinical research may be conducted if the medicinal product acts differently than expected.（2）Phase 1Typically, Phase 1 or FIH trials represent the initial human exposure to an investigational medicine. The FIH trial of a new treatment, which has been determined to be safe (non-toxic) for use in animals, is usually conducted in a small group of healthy human volunteers (i.e., 20-100 subjects). In some cases, e.g., for rare diseases, oncology products, or highly toxic treatments for fatal, unmet medical need, Phase 1 trials may also be conducted in patients with the disease.The main objective of Phase 1 is to establish a preliminary safety profile of the investigational medicinal product, to determine the highest dose that can be administered without causing harm, a maximum tolerated dose (MTD) in humans, and to show that participants can tolerate the investigational medicine. In addition, Phase 1 trials typically assess the pharmacodynamic (PD) or “what the drug does to the body” and pharmacokinetic (PK) profile or “what the body does to a drug” of the investigational medicine, which may also include specialized Phase 1 trials, e.g., radio-labeled studies to establish drug metabolism and other PK parameters, cardiovascular safety studies, hepatic and renal impairment studies, and drug-drug interaction studies. Phase 1 trials are used to determine the most appropriate delivery mechanism (e.g., pill, solution, injection), adequate dose, and administration schedule. Preliminary signs of efficacy are often observed in Phase 1 trials, although not the primary endpoint. Phase 1 typically lasts.（3）Phase 2Building on the results from Phase 1, in Phase 2 trials, the investigational medicine is administered to patients with the disease or condition for which the medicine is being developed. Phase 2 trials typically involve several hundred participants (100-300) at multiple sites and are designed to evaluate PD endpoints, determine preliminary evidence of efficacy, and identify an appropriate dose and administration schedule for evaluation and confirmation in Phase 3. Phase 2 typically lasts approximately 2 years. Phase 2 trials are typically referred to as non-pivotal or pilot trials. Sometimes, Phase 2 trials are separated into Phase 2a and 2b trials. Phase 2a focuses on dosing requirements, and Phase 2b specifically focuses on efficacy, e.g., treating, preventing, or diagnosing the disease. In Phase 2a, a small number of participants are administered the investigational medicine in increasing quantities after safety is confirmed at that dose to determine a dose-response relationship. That is, is there an increase in response that is correlated to the dose. Additionally, the frequency of dosing for the best response also is determined. This step is referred to as proof of concept (POC) or proof of principle (POP), linking Phase 1 and dose-finding studies. A POC study is an important clinical development success criterion because it demonstrates a measurable biological effect related to the target of interest. This effect may reasonably translate to a clinically meaningful effect in later-phase clinical trials.The primary purpose of Phase 2b, in a larger number of participants than 2a, is to find the optimal dose with minimal side effects (dose-response studies) while keeping the therapeutic benefit (efficacy), a critical step in the drug development continuum. It is referred to as the definitive dose range finding trial. Proper dosing is critical to the effectiveness of the medicine. Phase 2b clinical trials evaluate dose escalation as single ascending dose (SAD) and multiple ascending dose (MAD) trials to identify the optimal dosage and dosing schedule for confirmation in Phase 3 clinical trials.（4）Phase 3During Phase 3 trials, the investigational medicine is given to a much larger group of participants (300 to 3,000), depending on the condition being studied, to confirm its effectiveness, to monitor side effects, to compare it to the current standard of care, and to collect information to allow the product to be used safely. Phase 3 trials typically last approximately 1-4 years.Phase 3 trials are often randomized, multicenter trials and usually have a longer duration, sometimes lasting years (1-4). Randomized trials randomly assign participants to receive either the investigational agent or an approved medicine (often the standard of care) or placebo if no treatment exists for the investigational medicine. Phase 3 trials are typically double-blind; neither participants nor investigators know which treatment is assigned. Randomization helps eliminate bias in interpreting results. Phase 3 trials are the pivotal safety and efficacy trials supporting the commercial marketing authorization and labeling, defining the commercial dose and actual conditions of use. Because Phase 3 trials are more extensive and longer, the results are more likely to detect long-term or rare side effects. While Phase 3 trials often are referred to as pivotal or registrational trials, all data from Phase 1-3 are submitted for regulatory review.（5）Phase 4After authorization, postauthorization trials usually are carried out under the scope of postmarketing safety assessment or surveillance or as a result of a condition of authorization. Phase 4 trials also are conducted to gather more information on the drug’s desired and undesired effects, to check performance in real life and a larger user population, to identify long-term benefits and risks, and to identify any rare side effects. The trials may involve specific or varied patient populations (e.g., pregnant or nursing women) generally excluded from clinical trials or confirm side effects associated with its long-term use in the approved patient population. Where previous clinical trials were limited in thoroughly evaluating factors that could influence the drug’s performance, Phase 4 trials can be used to evaluate the factors more thoroughly. For example, clinical trial participants may be instructed to follow a strict diet and drug regimen. In contrast, Phase 4 trials are conducted on regular populations where various foods and other drugs may be taken.Phase 4 trials may also be used to find new applications for approved medicines (repurposing or reworking). Once identified, clinical trials to support new indications with approved drugs enter the drug development continuum at Phase 2 or Phase 3, depending on the indication and available supportive information.Because Phase 3 trials are conducted in well-controlled trials with a smaller population, previously unseen harmful effects can be seen in postauthorization trials. Medicines have been removed from the market based on new safety data not reported at the time of the original authorization and in the supportive Phase 3 trials. For example, the pain reliever rofecoxib (Vioxx) showed an increased relative risk for serious cardiovascular events, including heart attack and stroke, during long-term treatment (18 months) for a new indication during a Phase 3 trial. Merck and Co. subsequently announced a voluntary, worldwide withdrawal of Vioxx from the market.The results of Phase 3 confirmatory trials are key to moving to Step 4, Agency Review and marketing authorization. Clinical research and the clinical trial phases of the development continuum,including conduct and objectives, are discussed in more detail in Section 4.• Step 4: Agency Review and Marketing AuthorizationIf all the data and evidence from discovery and development, preclinical research, clinical research, and CMC (quality) development demonstrate that the medicine is safe and effective for its intended purpose and the product developer has fully characterized the medicine, including the quality, strength, purity, potency, and stability attributes, and the medicine can be reproducibly made, tested and supplied, the product development continuum moves to step 4, agency review and marketing authorization. In step 4, the sponsor compiles all the relevant information demonstrating that the medicinal product is safe and effective, and of appropriate quality and submits a marketing authorization application (MAA, also called a regulatory dossier) to a regulatory agency, e.g., US FDA, EMA, Brazilian Health Regulatory Agency (ANVISA), etc., requesting authorization to market the product. The MAA must include data and reports from pre-clinical research through Phase 3 confirmatory clinical trials and CMC information about the medicine following the rules and regulations of that region. There are over 150 regulatory agencies worldwide regulating healthcare products in individual regions.24 Each region has regulatory requirements to which the medicinal product must conform to gain authorization. This means developers and sponsors must understand each region’s requirements and create multiple documents for submission to the different regulatory agencies, adding to the complexity of product development.Recognizing the diversity in technical requirements from available internationally, in 1990, ICH brought together the regulatory authorities from the US, EU, and Japan, along with pharmaceutical industry representatives, to discuss scientific and technical aspects of pharmaceuticals with the objective to develop harmonized regulatory requirements and guidelines in these regions. Since then, ICH has developed numerous guidelines on safety, quality, and efficacy topics. The guidelines have been adopted by an increasing number of regulatory agencies worldwide. Now in its fourth decade, ICH is working to extend harmonization beyond the founding regions.The Common Technical Document (CTD), finalized in 2003, fostered considerable harmonization in the technical requirements for the authorization of medicinal products. The agreement to organize all safety, efficacy, and quality information in a common format to generate well-structured regulatory dossiers negated the need to reformat the information submitted to the different regulatory authorities. It is important to note that the CTD does not address the content of information to regulatory authorities. The CTD fundamentally changed the regulatory review process and practices. The CTD is the mandatory submission format for MAAs in major markets, including Canada, Japan, EU, US, and Australia. Other regions, including the Middle East and North Africa (MENA), are implementing CTD, including the successful implementation of the electronic CTD (eCTD) specification. For example, since 2015, Saudi Arabia, Jordan, and Qatar have implemented the eCTD format.The CTD is organized into five modules (see Figure 2-5). Module 1 is region-specific, providing information that cannot be harmonized. It includes administrative information such as application forms and labeling, including prescribing information and proposed labels for use in the region. Modules 2-5 are intended to be harmonized for all regions and make up the main body of the CTD. Module 2 contains the CTD summaries, which are basically overviews and summaries of Modules 3-5. Module 3 contains information on quality and CMC that describes how the medicinal product was developed, manufactured, controlled, and released in compliance with GMP and quality regulations. Module 4 contains nonclinical information, including study reports, and Module 5 contains clinical research information including study reports and the data from clinical trials that demonstrate safety and efficacy for its intended use. ICH has finalized guidelines for each discipline assigning codes to each category: Q (quality), S (safety), and E (efficacy).Also in 2003, the EMA began accepting eCTD, which became mandatory for centralized procedure applications in 2010. On 1 July 2015, the EMA announced it would no longer accept paper application forms for products applying to the centralized procedure.30 Other countries followed suit. In 2017, the US announced that all new drug submissions are required to be made in eCTD format.31 In Japan, the Pharmaceuticals and Medical Devices Agency (PMDA) issued an eCTD implantation guide in December 2017.32 Health Canada announced eCTD as mandatory as of January 1, 2018.33 The eCTD is increasingly becoming mandatory in different countries for various submission types.After the MAA is authored, formatted, compiled, and published following country-specific requirements, the eCTD allows for the seamless and automatic electronic submission of the CTD to the regulatory agency. The eCTD provides a harmonized technical solution to implementing the CTD electronically. Submission of the regulatory dossier is through a method “gateway” of securely providing regulatory dossiers for review, e.g., the EU e Submissions Gateway, the US Electronic Submission Gateway (ECG), and Health Canada’s Common Electronic Submission Gateway (CESG).After acknowledgment of receipt and validation by the regulatory agency that the regulatory dossier is complete for formal review, the dossier is accepted, and a holistic, rigorous review begins. An agency review team which may include scientists, chemists, biologists, pharmacologists, toxicologists, statisticians, and physicians, among other experts, begins to review the evidence generated by the application holder that demonstrates the quality, safety, and effectiveness of the medicine’s intended use and following proposed labeling. In addition to making key decisions regarding the medicine’s safety and effectiveness profile when used as intended, the CMC used to ensure and maintain product quality are assessed to demonstrate that the processes are adequate to preserve the identity, purity, strength, potency and microbial control throughout product use and expiry. Key to authorization is also demonstrating a favorable benefit-risk profile. For new molecular entities, prior to final authorization, the regulatory agency may require an inspection of the manufacturing facility to verify the quality information and to ensure the facility is compliant with cGMPs and is capable of manufacturing and supplying a safe medicine.Although global regulatory authorities share the same goal –protecting public health by regulating medicinal products – the processes and timelines for reviewing MAAs vary. The US and EU have the most advanced and defined regulatory systems in the world. In the US, review fees and times are defined and driven by the Prescription Drug and User Fee Act (PDUFA) for new molecular entities, the Biosimilar User Fee Amendments (BSUFA) for biosimilars, and the Generic Drug User Fee Act (GDUFDA) for generics.MAAs under regular review have an action date of 10 months; those under priority review have an action date of 6 months. The action date may be a decision to approve the drug, not approve it, or issuance of a complete response letter when more information and adequate review time are needed. In the EU, EMA has four registration pathways to MA depending on the type of product and the number of countries targeted; centralized, decentralized, national, and mutual recognition procedures.35 Evaluation of the MAA under the centralized procedure when used for authorization in the EU (27 member states) can typically take up to 210 days, not including pauses in the review cycle (clock stops) when applicants are asked to provide additional information from the Committee for Medicinal Products for Human Use (CHMP). CHMP is EMA’s scientific committee responsible for human medicines and prepares scientific opinions on whether the medicine may be authorized after a thorough evaluation of the MAA. Ultimately, the scientific opinion issued by CHMP is sent to the EMA.36 The EMA then sends the opinion to the European Commission (EC), which takes a decision to issue the MA if approved. Other regulatory agencies are improving and enhancing their regulatory systems, and the process of harmonization continues.One significant enhancement to the regulatory review process is the result of regulatory agencies recognizing that patients with serious or rare conditions can derive clinical benefit by gaining access to potential therapies more quickly than standard review times. Accordingly, regulatory authorities across the globe have developed expedited development and non-standard review and authorization pathways to facilitate the development of new medicines (e.g., futibatinib, pembrolizumab) for such conditions and an applicant may pursue more than one of expedited pathways in parallel. These pathways also encourage early and continued interactions between the medicinal product developer and the regulatory agencies.In the US, FDA has developed four programs, i.e., fast track designation, breakthrough therapy designation, accelerated authorization, and priority review designation, intended to facilitate and expedite the development and review of new drugs to address an unmet medical need in the treatment of a serious or life-threatening condition.Similarly, EMA instituted PRIME (PRIority MEdicines) to support the development of medicines that target an unmet medical need. Through PRIME, the agency offers early and proactive support to medicine developers to optimize the generation of robust data on a medicine’s benefits and risks and enable accelerated assessment of medicines applications.PMDA Japan developed the SAKIGAKE Designation System, promoting research and development and early clinical research/trials in Japan aiming at early practical application for innovative medical products with significant prospective efficacy by conducting priority consultations, prior assessments, and priority reviews and the Scheme for Rapid Authorization of Unapproved Drugs. More detail on expedited pathways is provided in Chapter 23.Receiving marketing authorization from any global regulatory authority is a significant milestone in a medicine developer’s product development continuum to provide therapeutics to treat large population segments affected by a given disease and developing pharmaceutical innovations targeting unmet medical needs (e.g., rare diseases) for patients around the world. This step leads to Step 5 in the product development continuum, Market Access, making the medicinal product available to the right patient at the right time and at the right price.• Step 5: Market AccessThe ultimate goal and focus of the medicinal product development continuum is gaining authorization and commercialization so that patients have access to a new, alternative treatment or one to meet an unmet medical need. For global pharmaceutical and biotechnology companies, this is market access, generally described as getting the right treatment, to the right patient, at the right time for the right price. Prescribers and patients need immediate, consistent, and continued access to medicines once approved and available. Often, market access and activities are planned closer to marketing application submission and authorization, and launch. However, to be successful, market access planning should be part of the process from early development through post-launch, providing input into the target product profile and other key development input, for example, patient preferences, quality-of-life metrics, health behaviors, symptoms, and health status.The important role of market access is illustrated in Figure 2-6. The simplified model shows the key considerations to market access between regulatory authorization and having the medicine prescribed. Although this model shows a sequential approach to market access after authorization, the reality is that for a successful market access strategy, the considerations need to be incorporated much earlier.Before the patient can access the medicine, regulatory authorization must be received from the health authority in a particular country or countries. Even when authorized, the medicine may not be immediately available to patients. In many countries, national pricing and reimbursement need to be determined first. Within the EU, for example, a marketing authorization is typically followed by health technology assessments (HTAs) at the national level, which are used to guide pricing and reimbursement recommendations. Reimbursement is not always guaranteed. For example, in January 2020, the UK National Institute for Health and Care Excellence (NICE) recommended against reimbursement for Spravato (esketamine) for treatment-resistant depression due to uncertainties over its clinical cost and effectiveness. More recently, in May 2022, the Canadian Agency for Drugs and Tech-nologies in Health (CADTH) recommended against reimbursement for Spinraza (nusinersen) for adults with spinal muscular atrophy based on the lack of clinical trials in SMA patients ages 18 and older.In addition, there can be a variety of decision-makers at the local, regional, or hospital levels. For example, a country may have 30 reimbursable licensed drugs available for a condition. However, if the local prescribing guidelines state that the patient cannot be prescribed one of the medicines, it is unlikely to be prescribed.Once these key elements are in place, then the physician or other prescriber plays a critical role in deciding which drug to prescribe to a patient based on several factors, including clinical guidelines, local formularies, and, when available, how a previous patient responded to a drug, treatment-related symptoms (side effects) and other available treatments. These factors may also include health-related quality of life (QoL), which can reflect a patient’s perception of their physical, psychological, social, and overall general well-being. In Italy and Spain, QoL data are important at the regional and local levels for inclusion in formularies and guidelines.The relationship between pricing and reimbursement to market success is shown in Figure 2-7. Pricing is the list price or the national price of the drug, the published price paid to the manufacturer. The price can be adjusted to include charges from wholesalers, negotiated discounts, incentives, and other agreements. In the US, the MAA holder sets the price without regulation. In many other countries, the price is set based on prices in other countries. For example, pricing in France, Germany, and the UK are commonly referenced and influence the price set in other countries.40 In the UK, reimbursement of medicines through the national health service (NHS) is influenced by the NICE), the Scottish Medicines Consortium (SMC), and the All Wales Medicines Strategy Group (AWMSG). In France, the Haute Autorité de Santé (HAS), the HTA determines the percentage of the price to be reimbursed by the government and paid by the patient. In China, there is currently no reimbursement. Medicines go straight to the free market, and patients pay the price.Reimbursement is also country specific. In many European countries, an HTA that measures the relative effectiveness assessment (REA) of a new drug compared to the standard of care is a requirement for reimbursement. The health-related QoL is a recognized REA endpoint. However, there is a lack of consensus on which QoL data to use, e.g., quality-adjusted life years or equal value of life years gained.While it is important to target the broadest market access possible, with the most favorable pricing, it is also important to define the value of the medicine to each stakeholder. Medicinal product development companies are now including real-world evidence (RWE) tools in the product lifecycle to help achieve launch success and optimal market access, positioning the right drug to the right patient. In simplest terms, RWE is informing and supporting decision-making across the product lifecycle using analytics that provide real-world knowledge on patients, different clinical phenotypes, and the burden of disease not possible in the past.39 In addition, RWE can facilitate comparative effectiveness, help determine new product insights, and differentiate products concerning broad-based outcomes such as medication adherence, patient satisfaction, resource utilization, and associated costs.44 These data are then used to inform the target product profile, define product specific-attributes, inform clinical trial design (right disease and patient population), and target specific markets. Clinicians and patients are also using RWE to understand advancement in care, efficiency, and health outcomes. Moving forward, RWE is a tool that is increasing in use across the drug development continuum to maximize value and increase the probability of market success.Market access, including pricing and reimbursement, advertising, and other factors that influence market success, are discussed in more detail in Chapter 31, Advertising and Promotion, and Chapter 32, Market Access: Reimbursement and Pricing.In parallel with market access, the MAA holder is responsible for postmarketing regulations and lifecycle management of the approved medicine. The MAA holder must ensure product quality, safety, and efficacy and mitigate any potential identified postmarket impact on patient health and safety through ongoing compliance with cGMP regulations and guidance related to quality systems, including product complaints. In addition, the MA holder must maintain the application up to date regarding labeling, CMC changes, e.g., manufacturing or formulation, and pharmacovigilance(safety), including adverse event reporting. These activities are typically categorized as postauthorization activities, discussed in more detail in Section 6: Postmarketing Authorization.二、ConclusionMedicinal product development is a continuum with specific steps that are globally recognized. The process is long, complex, costly, and made more challenging by the different country-specific requirements.ICH continues to work on harmonization of regulatory requirements and guidelines beyond the founding ICH regions, and emerging markets are adopting and implementing standards such as the CTD and eCTD submission formats, ICH E8(R1) on General Considerations for Clinical Studies and ICH E6(R2) Good Clinical Practice. CMC development is an integral part of the development continuum that ensures the quality, consistency, safety, and availability of the medicinal product.Regulatory agencies recognize the need to expedite the authorization and availability of medicinal products, especially for serious, life-threatening, rare, and orphan indications, while maintaining safety and effectiveness. Agencies such as FDA, EMA, and PMDA have worked to create and publish guidelines and approaches to expedite development programs and non-standard review and authorization pathways to facilitate the availability of new medicines. Agencies are encouraging early and frequent interactions for novel medicines and new indications.Marketing authorization is key to allowing medicines to be sold in the regions authorized. However, in many countries, national pricing and reimbursement need to be determined and agreed upon before the medicine is prescribed and patients can access the medicine. Often, decisions also are made at the local, regional, or hospital levels. Market success needs to take into account pricing, reimbursement, and stakeholder (payer, physician, and patient) needs. Health technology assessments, health-related quality of life metrics, and real-world evidence are playing important roles in the product development continuum and provide input to clinical trial design, target product profile, and more, helping to ensure the right drug is developed for the right patient at the right price.参考文献：（上下滑动查看更多）All references verified 5 January 2023.1. Food and Drug Administration. The Drug Development Process. Last updated 04 January 2018. https://www.fda.gov/patients/learn-aboutdrug-and-device-approvals/drug-development-process2. European Medicines Agency. From lab to patient: journey of a medicine. Last updated 10 February 2020. https://www.ema.europa.eu/en/about-us/what-we do/authorisation-medicines#from-lab-topatient3. Food and Drug Administration. Determining whether to submit an ANDA or 505(b)(2) application [guidance]. Issued May 2019. Last updated 03 March 2020. https://www.fda.gov/regulatory-information/ search-fda-guidance-documents/determining-whether-submit-andaor-505b2-application4. Official Journal of the EU. Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001. Last Updated01 January 2022. https://eur-lex.europa.eu/legal-content/en/TXT/?uri=CELEX%3A32001L00835. Food and Drug Administration. What Are Generic Drugs? Last Updated 24 August 2017. https://www.fda.gov/drugs/generic-drugs/what-are-generic-drugs6. European Medicines Agency. Generic and hybrid medicines. https://www.ema.europa.eu/en/human-regulatory/marketing-authorisation/generic-hybrid-medicines7. European Medicines Agency. Biosimilar Medicines: Overview. https://www.ema.europa.eu/en/humanregulatory/overview/biosimilarmedicines-overview8. Food and Drug Administration. Biosimilars and Interchangeable Biologics. More Treatment Choices. Content current as of 12 October 2021. https://www.fda.gov/consumers/consumer updates/biosimilarand-interchangeable-biologics-more-treatment-choices9. European Medicines Agency. Omnitrope. 12 April 2006. https://www.ema.europa.eu/en/medicines/human/EPAR/omnitrope#authorisationdetails-section10. Drug@FDA. BLA 125553 Approval Letter, 06 March2015. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2015/125553Orig1s000ltr.pdf11. Quartz. Viagra’s famously surprising origin story is actually a pretty common way to find new drugs. 10 September 2017. https://qz.com/1070732/viagras-famously-surprising-origin-story-is-actuallya-pretty-common-way-to-find-new-drugs12. Kim JH, Scialli AR. Thalidomide: the tragedy of birth defects and theeffective treatment of disease. Toxicol Sci. 2011 Jul;122(1):1-6. doi:10.1093/toxsci/kfr088. Epub 2011 Apr 19. Erratum in: Toxicol Sci. 2012 Feb;125(2):613. PMID: 21507989.13. 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What is market access? https://www.prmaconsulting.com/blog/what-is-market-access/. Accessed 21 October 2022.41. National Institute of Health and Care Excellence. 28 January 2020. Nasal spray medicine for treatment-resistant depression not recommended by NICE.https://www.nice.org.uk/news/article/ nasal-spray-medicine-for-treatment-resistant-depression-notrecommended-by-nice42. Gardiner RB, Sealey S, Edathodu A, Makku SR. The real impact of quality of life (QoL) endpoints on market access decisions across markets - a case study of oncology products. Value in Health.2014;17(3):PA94-A95. https://doi-org.libproxy1.nus.edu.sg/10.1016/j.jval.2014.03.55043. Kleijnen S et al. The impact of quality-of-life in relative effectiveness of new anti-cancer drugs in European countries. Qual Life Res 2017;26(9):2479-2488. doi: 10.1007/s11136-017-1574-944. PharmaVoice. Ask the experts: How does real world evidence ensure market access? March 1, 2020. https://www.pharmavoice.com/news/2020-03-rwe experts/612296/声明：原英文原文版权归美国法规事务协会（RAPS）所有，本译文供参考，如有任何建议，请联系我们。更多优质内容，欢迎关注↓↓↓
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